Tuberous sclerosis complex (TSC) is an autosomal dominantly inherited neurocutaneous disorder caused by inactivating mutations in TSC1 or TSC2, key regulators of the mechanistic target of rapamycin complex 1 (mTORC1) pathway. In the CNS, TSC is characterized by cortical tubers, subependymal nodules and subependymal giant cell astrocytomas (SEGAs). SEGAs may lead to impaired circulation of CSF resulting in hydrocephalus and raised intracranial pressure in patients with TSC. Currently, surgical resection and mTORC1 inhibitors are the recommended treatment options for patients with SEGA. In the present study, high-throughput RNA-sequencing (SEGAs n = 19, periventricular control n = 8) was used in combination with computational approaches to unravel the complexity of SEGA development. We identified 9400 mRNAs and 94 microRNAs differentially expressed in SEGAs compared to control tissue. The SEGA transcriptome profile was enriched for the mitogen-activated protein kinase (MAPK) pathway, a major regulator of cell proliferation and survival. Analysis at the protein level confirmed that extracellular signal-regulated kinase (ERK) is activated in SEGAs. Subsequently, the inhibition of ERK independently of mTORC1 blockade decreased efficiently the proliferation of primary patient-derived SEGA cultures. Furthermore, we found that LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5 were overexpressed at both gene and protein levels in SEGA compared to control tissue. Taken together LAMTOR1-5 can form a complex, known as the 'Ragulator' complex, which is known to activate both mTORC1 and MAPK/ERK pathways. Overall, this study shows that the MAPK/ERK pathway could be used as a target for treatment independent of, or in combination with mTORC1 inhibitors for TSC patients. Moreover, our study provides initial evidence of a possible link between the constitutive activated mTORC1 pathway and a secondary driver pathway of tumour growth.

• MeSH
• adaptorové proteiny signální transdukční genetika   metabolismus   MeSH
• astrocytom etiologie   genetika   metabolismus   MeSH
• astrocyty účinky léků   metabolismus   MeSH
• butadieny farmakologie   MeSH
• dítě MeSH
• dospělí MeSH
• extracelulárním signálem regulované MAP kinasy antagonisté a inhibitory   genetika   metabolismus   MeSH
• hamartin genetika   MeSH
• inhibitory enzymů farmakologie   MeSH
• intracelulární signální peptidy a proteiny genetika   metabolismus   MeSH
• kojenec MeSH
• lidé MeSH
• MAP kinasový signální systém genetika   MeSH
• mechanistické cílové místo rapamycinového komplexu 1 MeSH
• messenger RNA metabolismus   MeSH
• mikro RNA metabolismus   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádorové buňky kultivované MeSH
• nádory mozku komplikace   genetika   metabolismus   MeSH
• nitrily farmakologie   MeSH
• předškolní dítě MeSH
• sekvenční analýza RNA MeSH
• sekvenování transkriptomu MeSH
• stanovení celkové genové exprese MeSH
• tuberin genetika   MeSH
• tuberózní skleróza komplikace   genetika   MeSH
• výměnné faktory guaninnukleotidů genetika   metabolismus   MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH